Levofloxacin, (S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid has the formula as given below

Levofloxacin is the S-enantiomer of Ofloxacin, a fluoroquinolone antibacterial agent. The mechanism of action of Levofloxacin and other fluoroquinolone antibacterials involves the inhibition of DNA gyrase (bacterial topolsomerase II), an enzyme required for DNA replication, transcription repair and recombination.
U.S. Pat. No. 4,383,892 discloses the pyrido [1,2,3-de][1,4] benzoxazine derivatives and methods for preparation of them.
U.S. Pat. No. 5,053,407 discloses the optically active pyridobenzoxazine derivatives, intermediates useful for preparation of pyridobenzoxazine derivatives and the process.
U.S. Pat. No. 5,051,505 discloses the process for preparation of piperazinyl quinolone derivatives by reaction of dihaloquinolones with piperazine derivatives and tetra alkyl ammonium halides in presence of a polar solvent such as acetonitrile, DMF, pyridine, sulfolane and DMSO. U.S. Pat. No. 5,155,223 discloses the process for preparation of quinoline carboxylic acids.
Three polymorphic forms of levofloxacin i.e. anhydrous levofloxacin form α, β, γ and two hydrate forms i.e. hemihydrate and monohydrate are reported in the literature.
U.S. Patent Application No. 2003/130507 discloses the process for preparation of levofloxacin by reaction of (S)-(-) 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4] benzoxazine-6-carboxylic acid with N-methyl piperazine in a polar solvent or as a neat mixture at an elevated temperature of 70° C. to 120° C. and recovering levofloxacin by using the techniques well known in the art. The Application further discloses the polymorphic or pseudomorphic forms (form-A, form-B, form-C, form-F, form-G, form-H) of levofloxacin and the processes for their preparation.
EP Patent No. 444,678 and U.S. Pat. No. 5,545,737 are particularly disclosed the processes for preparation of hemihydrate free of monohydrate by crystallizing crude levofloxacin in aqueous ethanol containing 2-10% moisture content and process for monohydrate free of hemihydrate by crystallizing crude levofloxacin in aqueous ethanol containing 10% or more than 10% moisture content.
Surprisingly, the inventors observed that when the water content is varied or by addition of water to the slurry of levofloxacin in a polar solvent at the reflux temperature of the solvent, levofloxacin hemihydrate free of the monohydrate resulted.